Placental hypoxia contributes to major pregnancy complications such as intrauterine growth restriction (IUGR) and preeclampsia (PE). Globally, ~10% of all maternal/fetal deaths and ~ 20% of all NICU admissions are due to PE and/or IUGR. Fetoplacental hypoxia also increases the risk of coronary heart disease, type 2-diabetes, hypertension and stroke later in life. These major human health problems require new paradigms for understanding and resolution. Our goal is to identify evolved adaptations that protect the fetus from an adverse environment (hypoxia) within a particular organ system, the human placenta. The 4-group research design compares Andeans (altitude-adapted for ~8000 yr) versus altitude-naove (European) groups living at high versus low altitude. We are using an approach previously untested in the setting of recent human evolution, one of potentially high translational impact. This exploratory project will advance the fields of perinatal biology and evolutionary genetics forward in three ways. First we use a reverse engineering approach: rather than ask what causes disease, we ask what permits normal function under conditions that would normally increase disease risk. Identification of placental genes and systems that have been altered under the selective pressure of chronic (altitude-induced) hypoxia will demonstrate the utility of this approach. Second, for the first time, we apply analyses originally developed to detect genetic variation due to evolutionary forces between species to a within-species (human), organ specific (placenta) model in which the negative selective pressure (hypoxia) is known. Third, we seek to link the genetic variation detected with the physiological advantages we have previously identified as contributing to improved fetal growth and pregnancy outcome among the adapted Andean population. We will test this preliminarily in this proposal, and mechanistically in our future work. We can demonstrate the utility of this novel approach within the 2-year project because we already have an extensive clinical database, placental tissue and DNA from >200 pregnancies of known, genetically verified bio-geographic ancestry. The specific aims are: 1) Assess gene expression differences between adapted vs. altitude native groups in ~1500 genes expressed in human placenta previously identified as recently and adaptively evolving, and in those that we have identified as candidate genes based on our physiological studies of placental function; 2) Identify the source of the expression differences identified in Aim 1 by testing whether they are due to genetic or epigenetic effects. Our analytical approach includes tests designed to reveal the degree to which genes have been under selective pressure, permitting us to isolate effects due to ancestry vs. environment. The translational promise of such work is that we will identify adaptive evolutionary responses to hypoxic stress that can then be evaluated for therapeutic relevance in the treatment of pathological conditions at sea level. ) PUBLIC HEALTH RELEVANCE: Abnormalities of human fetal growth cost billions of dollars per year in intensive care for newborns and subsequent medical and social costs due to disabilities. This project is designed to discover placental genes that have specifically evolved to protect babies in utero from the consequences of not enough oxygen in the placenta. This will provide us with a map for the development of clinical tests that detect when babies in utero are not growing normally and to design therapies to improve their growth and long-term health.